EP2512648B1 - Nanoemulsion, verfahren zur deren herstellung sowie ihre verwendung - Google Patents

Nanoemulsion, verfahren zur deren herstellung sowie ihre verwendung Download PDF

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EP2512648B1
EP2512648B1 EP09805858.9A EP09805858A EP2512648B1 EP 2512648 B1 EP2512648 B1 EP 2512648B1 EP 09805858 A EP09805858 A EP 09805858A EP 2512648 B1 EP2512648 B1 EP 2512648B1
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nanoemulsion
phase
nanoemulsion according
lipid
aqueous phase
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EP2512648A1 (de
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Andrea Fratter
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Emultec Srl
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Emultec Srl
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
    • C09K23/017—Mixtures of compounds
    • C09K23/018—Mixtures of two or more different organic oxygen-containing compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
    • A23D7/0053—Compositions other than spreads
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/01—Other fatty acid esters, e.g. phosphatides
    • A23D7/011—Compositions other than spreads
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3481—Organic compounds containing oxygen
    • A23L3/3508—Organic compounds containing oxygen containing carboxyl groups
    • A23L3/3517—Carboxylic acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/21—Emulsions characterized by droplet sizes below 1 micron

Definitions

  • the object of the present invention is a stable nanoemulsion with a reduced micelle size, a composition comprising such a nanoemulsion and a method for the preparation thereof.
  • the nanoemulsion described herein is particularly, but not exclusively, used in the pharmaceutical, cosmetic, and foodstuff fields.
  • the nanoemulsions are heterogeneous polyphasic systems wherein at least one phase is dispersed in the form of nano-particles (nanodroplets) in the outer continuous aqueous phase.
  • nano-particles nanodroplets
  • the presence of a surface-active system which is capable of decreasing the interface tension that is very high in these systems, is essential due to the high number of dispersed-phase particles.
  • the surfactant creates an amphiphilic crown on the surface of the dispersed-phase droplets, thereby reducing the interface tension.
  • the nanoemulsions Due to the reduced micelle diameter that minimises the possibility of interaction with light and ultraviolet quanta (hv), the nanoemulsions appear transparent and translucent and take on a characteristic "bluish Tyndall” colouring, characterised by a tendency to opalescent blue.
  • the Tyndall effect is a light dispersion phenomenon due to the presence of dispersed particles with a size comparable to that of the incident light wavelength. Thus, in such dispersions, the incident light is reflected in every direction.
  • the tight connection between the inner phase micelle radius and the inner and outer differential pressure is inferred, which is expressed as the required force to be applied to the biphasic system in order to minimise the radius and interface tension of the micelle itself.
  • the pressure being inversely proportional to the radius, increases with the decrease of the latter and thus the ⁇ P value corresponds to the pressure to be overcome in order to decrease the particle size. For this reason, not only high concentrations of surfactants that decrease the interface tension must be used, but also considerable kinetic and thermal forces must by applied in order to reach a stability.
  • This rule regulates the sedimentation rate for a supposedly spherical particle, pointing out that the sedimentation rate is proportional to the size of the dispersed particle and thus confirming the importance of the surface-active system.
  • the nanoemulsions as they are not equilibrium systems, can not form spontaneously because the system attains a thermodynamic stability only if the interface tension reaches values that are sufficiently low such that the positive interface energy can be compensated for.
  • the known methods for the formation of nanoemulsions are of a mechanical type and comprise the use of high-energy instruments such as, for example, high-energy mixers, high-pressure homogenizers, or ultrasounds. Using such instruments allows to deform the forces that keep the particles joined, such that they can break into smaller units.
  • high-energy instruments such as, for example, high-energy mixers, high-pressure homogenizers, or ultrasounds.
  • Using such instruments allows to deform the forces that keep the particles joined, such that they can break into smaller units.
  • One first method of this kind is based on the so-called “Taylor instability” and consists in modifying the formulation such that the micro-emulsion particles merge and break into smaller particles at the time when the interface tension is increased.
  • the method turns out to be rather complex.
  • the droplets tend to combine rapidly, thereby forming bigger drops. It is however possible to obviate this phenomenon by exploiting the Phase Inversion Temperature (PIT), thanks to which a liquid crystal layer can form, which is able to encapsulate the droplets.
  • PIT Phase Inversion Temperature
  • a second type of method exploits phase inversion.
  • One first possibility is based on the so-called “catastrophic phase inversion”, wherein an emulsion containing water-in-oil drops suddenly turns into an oil-in-water dispersion or vice versa.
  • Recent researches have shown that in some cases such an inversion can occur by passing through an intermediate structure designated as “multiple emulsion”, wherein the continuous phase is able to deform and create smaller drops embedded in the bigger ones. When this multiple emulsion finally breaks it can release small droplets.
  • the second possibility is instead based on the traditional phase inversion, wherein the spontaneous reorganisation of the surfactant micelles is exploited.
  • the size of the droplets within the nanoemulsions is so small that gravity has no effect on them: they will not sediment until the drop size increases by coalescence through Brownian motions or other processes called "Ostwald ripening", which are controlled by the pressure gradient of Laplace rule existing among droplets of different sizes.
  • Such sedimentation mechanisms can be, as previously already stated, inhibited by using a set of appropriate solvents and preparing an emulsion the most monodispersed as possible.
  • WO2007/003565 discloses an emulsion , wherein the average particle size of the disperse phase is 500nm or less.
  • This emulsion contains as emulsifying agents ascorbylpalmitate (ASP) and one or more polyoxyethylenated sorbitan esters (ESP), a base like sodium hydroxide to improve the efficacy of ascorbylpalmitate but also a further emulsifying agents i.e. a sugar fatty acid ester.
  • ASP ascorbylpalmitate
  • ESP polyoxyethylenated sorbitan esters
  • a base like sodium hydroxide to improve the efficacy of ascorbylpalmitate but also a further emulsifying agents i.e. a sugar fatty acid ester.
  • WO2004/000274 discloses nanoemulsions comprising melatonin or liposoluble vitamins.
  • WO2007/060177 discloses nanoemulsions prepared by pouring the lipid phase into water by using high (ultrasound) energy instruments.
  • the main task of the present invention is to provide a stable nanoemulsion having a reduced micelle diameter.
  • one object of the invention is to provide a nanoemulsion that can be manufactured with a reduced energy waste in terms of agitation and heating energy.
  • Another object of the invention is to provide a nanoemulsion with the ability to carry active principle molecules of interest in the pharmaceutical, cosmetic or foodstuff field.
  • Still another object of the present invention is to provide a nanoemulsion that is also able to carry thermolabile or oxidation- and destabilization-sensitive active principle molecules.
  • the present invention intends to provide a nanoemulsion, the transparency and viscosity of which can be easily modulated so as to make the nanoemulsion itself suitable for a number of types of application.
  • the present invention has the object of providing a method for the manufacture of a nanoemulsion as described herein.
  • the invention has the object of providing a nanoemulsion and a method for the preparation thereof, which are highly reliable, relatively easy to perform, and cost-effective.
  • nanoemulsion comprising an aqueous phase and a lipid phase, which has a micelle size from 20 to 900 nm, as claimed in the attacked claims 1-12,
  • the task and the objects of the invention are also obtained by a method for the preparation of a nanoemulsion having a micelle size from 20 to 900 nm, comprising the steps of:
  • step (d) is performed by abruptly cooling the system under forced circulation of cold water, so as to reach a temperature ⁇ 30°C as fast as possible, preferably within 60 minutes from the emulsification.
  • the task and the appointed objects are also attained by a pharmaceutical, cosmetic or foodstuff composition comprising the nanoemulsion herein described.
  • the amount of each substance composing the nanoemulsion is indicated in terms of weight percentage of the substance or component based on the weight of the nanoemulsion (% w/w), unless differently stated.
  • the present invention relates to a nanoemulsion having a reduced micelle diameter and a method for the preparation thereof.
  • the association of two different emulsifying agents i.e. the ascorbyl palmitate d1) and the one or more polyoxyethylene sorbitan ester d2) allows to provide a nanoemulsion having a micelle diameter from 20 to 900 nm, preferably from 20 to 200 nm, even more preferably from 20 to 100 nm, with a reduced energy consumption in terms of agitation and heating energy.
  • the nanoemulsion is achievable by mixing an aqueous phase comprising ascorbyl palmitate and a lipid phase comprising one or more polyoxyethylene sorbitan esters.
  • ascorbyl palmitate is comprised in both the aqueous phase and the lipid phase.
  • Ascorbyl palmitate is the ester of L-ascorbic acid and palmitic acid (C16H3202). This compound is used in the cosmetic and foodstuff fields as an antioxidant and stabilising agent in emulsified systems, particularly as an anti-rancid antioxidant for fats (E304). In cosmetics, ASP is also used as a dermal-absorbable form of L-ascorbic acid.
  • ASP d1) is used as a co-emulsifier in combination with one or more polyoxyethylene sorbitan esters d2), in a concentration substantially higher than that needed for its anti-oxidising action in the same system.
  • ASP as a co-emulsifier has the advantage of allowing for the achievement of the nanoemulsion by applying a decreased thermal and mechanical energy, in particular without requiring the use of high-pressure turbo-emulsifiers and/or homogenisers, or the application of ultrasounds, as the so prepared chemo-physical system can be substantially considered as auto-emulsifying.
  • ASP behaves as a surfactant molecule by virtue of its amphiphilic structure deriving from the concomitant presence of a hydrophilic portion (L-ascorbic acid) and a lipophilic portion (palmitic acid) in the molecule.
  • ASP in an aqueous dispersion gives rise to micelle clusters having different geometries as a function of concentration.
  • Such micelle clusters are able to incorporate molecules insoluble or sparingly soluble in water (The thermotropic phase behavior of ascorbyl palmitate: an infrared spectroscopic study Helmut Sapper, David G. Cameron, and Henry H. Mantsch Can. J. Chem./Rev. can. chim. 59(16): 2543-2549 ).
  • ASP is sparingly soluble and, at concentrations of 2-3%, it is possible to resort to high temperatures for dissolution.
  • the dispersion Upon standing, depending on concentration, the dispersion gives rise to a yellow dense gel or "coagel", a solid-consistency white layer that may be reconverted into a liquid micelle dispersion (clear yellow) by mild heating. Since the ASP molecule exhibits two acidic hydroxyls (enediol), it is possible, in an aqueous dispersion, to give rise to clear solutions even without heating by formation of an ASP salt by adding an alkaline substance (base).
  • the aqueous phase of the nanoemulsion described herein also comprises a base, preferably in a quantity sufficient to induce ASP ionization and aid its dissolution in water and subsequent emulsifying action when in contact with the lipid phase.
  • the base may be an organic substance, such as for example L-arginine, L-lisine, a peptide or aminomethylpropanol (AMP), or an inorganic substance, such as an alkaline or alkaline earth metal hydrate, for instance NaOH, KOH, Ca(OH)2, or Ba(OH)2.
  • the metal hydrates are used in a diluted form in aqueous solutions, for example at 30% w/w.
  • the nanoemulsion may comprise ascorbyl palmitate in a quantity from 0.3 to 2% w/w, preferably from 0.5 to 1% w/w, even more preferably 0.75% w/w.
  • Polyoxyethylene sorbitan esters are non-ionic surfactant molecules characterized by a high hydropbilic-lipophilic balance (HLB), also referred to as polysorbates or TWEEN. These molecules are used in the cosmetic, pharmaceutical and foodstuff fields in emulsifying systems of the oil-in-water type because of their low toxicity profile, high application versatility, and neutrality with regard to the organoleptic and chemo-physical properties thereof.
  • HLB hydropbilic-lipophilic balance
  • the nanoemulsion may comprise one or more polyoxyethylene sorbitan esters in a quantity from 0.2 to 10% w/w, preferably from 2% to 10%w/w.
  • the one or more polyoxyethylene sorbitan esters may be selected from the group consisting of polyoxyethylene-(20)-sorbitan monolaurate (polysorbate 20), polyoxyethylene-(20)-sorbitan monopalmitate (polysorbate 40), polyoxyethylene-(20)-sorbitan monostearate (polysorbate 60), polyoxyethylene-(20)-sorbitan tristearate (polysorbate 65), and polyoxyethylene-(20)-sorbitan monooleate (polysorbate 80).
  • the polyoxyethylene sorbitan ester is polysorbate 60.
  • the emulsifying composition may further comprise glycomacropeptide (GMP).
  • GMP glycomacropeptide
  • GMP is a glycopeptide, a purified casein :fraction, obtained by treating cow's milk with chymosin during the manufacture of cheese.
  • the glycosilation portion is represented by sialic acid and it accounts for approximately 8% in weight of GMP.
  • MP as the proteins in general, is capable of performing an emulsifying action ascribed to the concomitant presence in the molecule of a lipophilic backbone of carbon atoms and functional hydrophilic groups along such a backbone, among which carboxyl groups and amino groups, which can form salts.
  • GMP may be used as an ASP and ESP co-adjuvant in the nanoemulsion described herein.
  • GMP maybe comprised in the nanoemulsion in a quantity from 0.2 to 5% w/w.
  • the aqueous phase of the nanoemulsion may further comprise a preserving agent.
  • the preserving agent may be, for example, selected from the group consisting of potassium sorbate, sodium benzoate, parabens, and mixtures thereof.
  • the lipid phase of the nanoemulsion may comprise one or more triglyceride lipids with different carbon chain lengths, preferably two lipids.
  • lipids maybe the products known by the trademarks Migliol 810, Migliol 812, Delios C, Delios V or Cetiol LC, all from Cognis.
  • the one or more lipids may be selected from the group consisting of coconut oil, wheat germ oil, sunflower oil, olive oil, and a medium-chain triglyceride. More preferably, the lipid is a medium-chain triglyceride (MCT). Particularly, the medium-chain triglyceride may be a C8-C10 triglyceride (caprylic-capric triglyceride), for example derived from coconut oil.
  • MCT medium-chain triglyceride
  • the medium-chain triglyceride may be a C8-C10 triglyceride (caprylic-capric triglyceride), for example derived from coconut oil.
  • the lipid phase of the emulsion may be represented by, or comprise, oils extracted from fish or algae rich in omega-3 fatty acids, such as EPA and DHA in various ratios.
  • the lipid phase may be made up of oils titrated in EPA and DHA contained in various ratios.
  • the one or more above-mentioned lipids may be used in a quantity ranging from 0.1 to 10% w/w of the nanoemulsion, more preferably from 0.5 to 5.0% w/w.
  • One or more further plant essential oils may be introduced into the lipid phase in concentrations ranging from 0.05 to 5% w/w, based on the nanoemulsion.
  • the one or more lipids may be used in a quantity from 0.1 to 10% w/w of the nanoemulsion, more preferably from 0.5 to 5.0% w/w.
  • the lipid phase of the nanoemulsion may further comprise one or more polyols in a quantity from 0.1 to 40% w/w, more preferably from 0.5 to 20% w/w, based on the nanoemulsion.
  • the one or more polyols may be, for example, selected from the group consisting of glycerine, propylene glycol, sorbitol, mannitol, fructose, sucrose, glucose, trehalose, and honey, and mixtures thereof.
  • the nanoemulsion according to the invention may be used in the manufacture of compositions, for instance in the foodstuff, pharmaceutical or cosmetic fields. Therefore, in a further embodiment, the nanoemulsion may also comprise one or more active principles in a quantity from 0.1 to 10% w/w, preferably from 0.1 to 5%.
  • the one or more active principles may be of a hydrophilic, lipophilic or amphiphilic nature, and depending on such a nature, maybe comprised in the lipid or aqueous phase of the nanoemulsion.
  • the one or more active principles may be selected from the group consisting of flavonoids, flavones, flavanones, isoflavones, essential oils, plant terpenes and saponins, liposoluble vitamins, vitamin cofactors, enzyme cofactors, amino acids, oligopeptides, peptides, unsaturated fatty acids, and pharmaceutical active principles.
  • the vitamin and enzyme cofactors maybe, for example, lipoic acid, coenzyme Q10 and its derivatives.
  • the nanoemulsion comprises ESP and ASP as an emulsifier and co-emulsifier, respectively (as the sole emulsifying agents), in combination with essential oils and/or terpenes.
  • the nanoemulsion may be, for example, characterized by a basic or slightly acidic pH, between 5 and 7, at which a high transparency is obtained, due to an increased surfactant action of ASP that, in such a range, results completely ionized within the hydroxylic portion.
  • the increase in transparency is accompanied by a decrease in the micelle diameters and viscosity.
  • the decreased viscosity allows to attain a nanoemulsion, the fluidity of which makes it comparable to a liquid system that may be atomized as a spray, increasing the indications and uses of the nanoemulsion.
  • the alteration in transparency and viscosity of the nanoemulsion according to the invention is a phenomenon that is repeatedly reversible by changing the pH and concomitantly the ionization of ASP.
  • the nanoemulsion may comprise chitosan preferably introduced as an acidic solution (pH ⁇ 4.5).
  • chitosan behaves as a polycation and, when an acidic chitosan solution is added to the nanoemulsion, formation of ionic bonds is noted between chitosan and the ascorbyl palmitate anionic molecules within the surface of the dispersed oil micelles. The establishment of such bonds then results in the formation of a coating by electrodeposition, the presence of which advantageously makes the nanoemulsion gastro-resistant.
  • the present invention also relates to a method for the manufacture of a nanoemulsion with a micelle size from 20 to 900 nm.
  • the emulsification occurs by phase inversion exploiting the Phase Inversion Temperature (PIT) with the aid of a mechanical stirring device and by administering thermal energy to the system.
  • PIT Phase Inversion Temperature
  • the first step of the method comprises setting up separately an aqueous phase comprising a base and a lipid phase comprising one or more polyoxyethylene sorbitan esters.
  • aqueous phase and the lipid phase comprise ascorbyl palmitate.
  • the two phases are heated at a temperature from 30 to 80°C, preferably from 40 to 70°C.
  • the aqueous phase is poured out into the lipid phase under mechanical stirring, so as to obtain the nanoemulsion.
  • the so-obtained nanoemulsion is abruptly cooled down bringing the temperature of the nanoemulsion to room temperature (25°C), for instance placing the nanoemulsion into a cold water bath.
  • the inventors of the present invention found out that using a combination of ascorbyl palmitate and one or more polyoxyethylene sorbitan esters allows for the manufacture of a nanoemulsion even at low temperatures, and anyway below 80°C, simply by mechanical stirring incorporating the aqueous phase into the oily phase. In this way, it is possible to reduce the consumption of energy in terms of thermal and mechanical energy to be provided in order to obtain emulsification. Furthermore, thanks to the possibility of operating at low temperatures (30-40°C), the method according to the invention also allows for the emulsification of thermolabile or oxidation- and destabilization-sensitive active principles selected from, liposoluble vitamins, and melatonin,
  • one or more active principles may be added to the aqueous and/or lipid phases during their preparation.
  • the method may comprise the further step of (d) dispersing one or more active principles into the nanoemulsion by mechanical stirring.
  • a nanoemulsion was prepared with the components indicated in Table 1, wherein the amounts of the single components are expressed as w/w percentage per 100 grams of nanoemulsion, unless differently indicated.
  • the lipid phase was prepared by vigorously stirring a medium-chain triglyceride (Delios V), ascorbyl palmitate, polysorbate 60, and glycerine, until a homogenous mixture was obtained.
  • the aqueous phase was prepared by melting fructose and the preserving agents in water under stirring, adding ascorbyl palmitate and thereafter the NaOH solution, until a pH value of 7 and a progressive clearness of the phase were reached.
  • the two phases were heated up to 50°C, to then start the emulsification under mechanical stirring (mechanical stirrer provided with a helical rotating rod, 10000 rpm), pouring out small sequential volumes of the lipid phase into the aqueous phase.
  • mechanical stirring mechanical stirrer provided with a helical rotating rod, 10000 rpm
  • the so-obtained nanoemulsion was cooled down to 25°C and the pH adjusted between 4 and ⁇ 4.5 with an 80% lactic acid solution or with citric acid.
  • the so-prepared nanoemulsion is stable, translucent, pale yellow, and has a pH between 4.0 and 4.5.
  • the dimensional analysis of the particles was carried out by Dynamic Back Scattering, showing a micelle diameter within the range from 30 to 50 nm, both at time 0 from the emulsification and two weeks after the manufacture of the nanoemulsion.
  • a nanoemulsion was prepared with the components indicated in Table 2, wherein the amounts of the single components are expressed as w/w percentage per 100 grams of nanoemulsion, unless differently indicated.
  • the lipid phase was prepared by vigorously stirring a medium-chain triglyceride (Delios V), ascorbyl palmitate, polysorbate 60, and glycerine, until a homogenous mixture was obtained.
  • the aqueous phase was prepared by melting fructose and the preserving agents in water under stirring, adding ascorbyl palmitate and thereafter the NaOH solution, until a pH value of 7 and a progressive clearness of the phase were reached.
  • the two phases were heated up to 50°C, to then start the emulsification under mechanical stirring (mechanical stirrer provided with a helical rotating rod, 10000 rpm), pouring out small sequential volumes of the lipid phase into the aqueous phase.
  • mechanical stirring mechanical stirrer provided with a helical rotating rod, 10000 rpm
  • the so-obtained nanoemulsion was cooled down to 25°C and the melatonin was dispersed by vigorous stirring. Once a homogeneous dispersion of the melatonin was induced, obtaining a translucent system devoid of suspended or sedimented clusters, the pH was adjusted between 4 and ⁇ 4.5 with an 80% lactic acid solution or with citric acid.
  • the so-prepared nanoemulsion is stable, translucent, pale yellow, and has a pH between 4.0 and 4.5.
  • the dimensional analysis of the particles was carried out by Dynamic Back Scattering, showing a micelle diameter within.the range from 30 to 50 nm, both at time 0 from the emulsification and two weeks after the manufacture of the nanoemulsion.
  • the nanoemulsion according to the invention fully performs the appointed duty, since the combination of ascorbyl palmitate and one or more polyoxyethylene sorbitan esters allows to obtain a stable nanoemulsion having a reduced micelle diameter.
  • the nanoemulsion according to the invention proved to be able to carry pharmaceutical, cosmetic or foodstuff active principles, including thermolabile or oxidation-sensitive active principles.
  • the method according to the invention allows to provide a stable nanoemulsion having a reduced micelle diameter, with a reduced consumption of energy in terms of thermal and mechanical energy, due to the combination of ascorbyl palmitate and one or more polyoxyethylene sorbitan esters.
  • the so-designed nanoemulsion, composition, and method are susceptible of numerous modifications and variations, all falling within the scope of the inventive concept; furthermore, all details may be substituted with other technically equivalent elements.

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Claims (14)

  1. Eine Nanoemulsion mit einer Micellgröße von 20 bis 900 nm, umfassend:
    a) einen interessierender Wirkstoff im pharmazeutischen, kosmetischen oder Lebensmittelbereich,
    b) eine wässrige Phase
    c) eine Lipidphase und
    d) Emulgatoren, wobei:
    • die wässrige Phase eine Base umfasst;
    • die Emulgatoren d) aus d1) Ascorbylpalmitat, d2) einem oder mehreren Polyoxyethylensorbitanestern und gegebenenfalls d3) Glykomacropeptid bestehen;
    • der eine oder die mehreren Polyoxyethylensorbitanester in der Lipidphase c) enthalten sind;
    • das Ascorbylpalmitat in der wässrigen Phase oder in der Lipidphase oder in beiden Phasen enthalten ist,
    • der Wirkstoff a) aus Melatonin und fettlöslichen Vitaminen ausgewählt wird.
  2. Nanoemulsion nach Anspruch 1, wobei sowohl die wässrige Phase als auch die Lipidphase Ascorbylpalmitat umfassen.
  3. Nanoemulsion nach Anspruch 1 oder 2, wobei Ascorbylpalmitat in einer Menge von 0,3 Gew.-% bis 2 Gew.-%, vorzugsweise von 0,5 Gew.-% bis 1 Gew.-%. vorliegt.
  4. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei der eine oder die mehreren Polyoxyethylensorbitanester in einer Menge von 0,2 Gew.-% bis 10 Gew.-%, vorzugsweise von 2 Gew.-% bis 5 Gew.-% vorliegen.
  5. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei der eine oder die mehreren Polyoxyethylensorbitanester aus der aus Polysorbat 20, Polysorbat 40, Polysorbat 60, Polysorbat 65 und Polysorbat 80 bestehenden Gruppe ausgewählt werden.
  6. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei die Micellgröße 20 bis 200 nm, insbesondere 20 bis 100 nm, beträgt.
  7. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei die Base aus der aus L-Arginin, L-Lysin, einem Peptid, Aminomethylpropanol, einem Alkalimetallhydrat, einem Erdalkalimetallhydrat und Mischungen davon bestehenden Gruppe ausgewählt wird.
  8. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei das Glykomakropeptid in einer Menge von 0,2 bis 5 Gew.-% enthalten ist.
  9. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, wobei die Lipidphase ein oder mehrere Lipide umfasst, die aus der aus Kokosnussöl, Weizenkeimöl, Sonnenblumenöl, Olivenöl und einem mittelkettigen Triglycerid, insbesondere ein C8-C10-Triglycerid und Mischungen davon bestehenden Gruppe ausgewählt werden.
  10. Nanoemulsion nach Anspruch 9, wobei das eine oder die mehreren Lipide in einer Menge von 0,1 bis 10 Gew.-%, insbesondere von 0,5 bis 5 Gew.-% vorliegen.
  11. Nanoemulsion nach einem oder mehreren der vorhergehenden Ansprüche, die ferner ein oder mehrere Polyole in einer Menge von 0,1 bis 40 Gew.-%, vorzugsweise von 0,5 bis 20 Gew.-%, enthält.
  12. Nanoemulsion nach Anspruch 11, wobei das eine oder die mehreren Polyole aus der aus Glycerin, Propylenglykol, Sorbit, Mannit, Fructose, Saccharose, Glucose, Trehalose und Honig bestehenden Gruppe ausgewählt werden.
  13. Verfahren zur Herstellung einer Nanoemulsion nach einem der Ansprüche 1 bis 12, mit einer Micellgröße von 20 bis 900 nm, der die folgenden Schritte umfasst:
    (a) Herstellen einer eine Base und wahlweise ein oder mehrere Polyole und den Wirkstoff umfassenden wässrigen Phase, und einer ein Lipid und einen oder mehrere Polyoxyethylensorbitanester umfassenden Lipidphase und wahlweise eines oder mehrerer ätherischen Öle und des Wirkstoffes, wobei die wässrige Phase oder die Lipidphase oder beide ferner Ascorbylpalmitat umfassen;
    (b) Erhitzen der wässrigen Phase und der Lipidphase bei einer Temperatur von 30 bis 80 °C, vorzugsweise von 40 bis 70 °C;
    (c) Ausgießen der wässrigen Phase in die Lipidphase unter mechanischem Rühren, um die Nanoemulsion zu erhalten; und
    (d) Bringen der Nanoemulsion auf Raumtemperatur.
  14. Verfahren nach Anspruch 13, gegebenenfalls umfassend einen Schritt (e) zur Dispersion des aktiven Bestandteils in die Dispersion durch mechanisches Rühren.
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